FIELD OF THE INVENTION
The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to selective xcex23 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.
The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. There are no currently approved medications that adequately treat either Type II diabetes or obesity. The invention described herein is directed toward an effective and timely treatment for these serious diseases.
One therapeutic opportunity that has been recently recognized involves the relationship between adrenergic receptor stimulation, anti-hyperglycemic effects, and metabolic events such as increased basil metabolic rate. Compounds that act as xcex23 adrenergic receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis, and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The xcex23 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the xcex21 and xcex22 receptor subtypes yet is considerably less abundant. The importance of the xcex23 receptor is a relatively recent discovery since the amino-acid sequence of the human receptor was only elucidated in the late 1980""s. A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the xcex23 receptor. Despite these recent developments there remains a need to develop a selective xcex23 receptor agonist which has minimal agonist activity against the xcex21 and xcex22 receptors.
The present invention provides methods of treating Type II diabetes, treating obesity, and stimulating the xcex23 receptor. In addition, the present invention also provides novel compounds that are selective xcex23 receptor agonists and as such are useful for treating Type II diabetes, obesity, and stimulating the xcex23 receptor. U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds, some of which are within the scope of formula I, as xcex2-adrenoceptor antagonists and vasodilators.
The present invention provides methods of treating Type II diabetes, treating obesity, and stimulating the xcex23 receptor which comprise administering to a patient in need thereof a compound described in Formula I below. 
wherein:
X1 is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, or a bond;
X2 is a bond, or a 1 to 5 carbon straight or branched alkylene;
X3 is O, S, or a bond;
R1 is a fused heterocycle of the formula: 
the A1 groups are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;
R2 is independently hydrogen, C1-C4 alkyl, or aryl;
R3 is hydrogen or C1-C4 alkyl;
R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of: 
R5 is hydrogen or C1-C4 alkyl;
R6 is hydrogen, C1-C4 alkyl, or CO2(C1-C4 alkyl);
or R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl;
or R6 combines with X2 and the carbon to which each is attached to form a C3-C8 cycloalkyl;
or R6 combines with X2, R4, and the carbon to which each is attached to form: 
provided that R5 is hydrogen;
R7 is independently hydrogen, halo, hydroxy, OR2, C1-C4 alkyl, C1-C4 haloalkyl, aryl, COOR2, CONR2R2, NHCOR2, C1-C4 alkoxy, NHR2, SR2, CN, SO2R2, SO2NHR2, or SOR2;
R8 is independently hydrogen, halo, or C1-C4 alkyl;
R9 is hydrogen, halo, hydroxy, CN, OR10, C1-C4 alkyl, C1-C4 haloalkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), SR2, CSNR2, CSNR11R12, NR2SO2R2, SO2R2, SO2NR11R12, SOR2, NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12;
R10 is C1-C4 alkyl, C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)n aryl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, (CH2)n optionally substituted heterocycle, or (CH2)nCO2R2;
R11 and R12 are independently hydrogen, C1-C4 alkyl, aryl, (CH2)naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
m is 0 or 1; and
n is independently 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
Another embodiment of the present invention is the genus of novel compounds defined by Formula II below. 
wherein:
X1 is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, or a bond;
X3 is O, S, or a bond;
R1 is a fused heterocycle of the formula: 
the A1 groups of said heterocycle are independently carbon or nitrogen, provided that no more than 2 nitrogens may be contained in either fused 6 membered ring and those 2 nitrogens may not be adjacent;
R2 is independently hydrogen, C1-C4 alkyl, or aryl;
R3 is hydrogen or C1-C4 alkyl;
R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of: 
X2 is a bond, or a 1 to 5 carbon straight or branched alkylene;
R5 is hydrogen or C1-C4 alkyl;
R6 is hydrogen, C1-C4 alkyl, or CO2(C1-C4 alkyl);
or R5 and R6 combine with the carbon to which each is attached to form a C3-C6 cycloalkyl;
or R6 combines with X2 and the carbon to which each is attached to form a C3-C8 cycloalkyl;
or R6 combines with X2, R4, and the carbon to which each is attached to form: 
provided that R5 is hydrogen;
R7 is independently hydrogen, halo, hydroxy, OR2, C1-C4 alkyl, C1-C4 haloalkyl, aryl, COOR2, CONHR2, NHCOR2, C1-C4 alkoxy, NHR2, SR2, CN, SO2R2, SO2NHR2, or SOR2;
R8 is independently hydrogen, halo or C1-C4 alkyl;
R9 is halo, CN, OR10, C1-C4 alkyl, C1-C4 haloalkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), SR2, CSNR2, CSNR11R12, NR2SO2R2, SO2R2, SO2NR11R12, SOR2, NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12;
R10 is C1-C4 alkyl, C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, (CH2)n optionally substituted heterocycle, or (CH2)nCO2R2;
R11 and R12 are independently hydrogen, C1-C4 alkyl, aryl, (CH2)naryl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl;
m is 0 or 1;
n is independently 0, 1, 2, or 3;
provided:
when R5 or R6 is hydrogen; either
1) one or more A1 must be nitrogen, or
2) R9 is CN, OR10, CO2R2, CSNR2, CSNR11R12, NR2SO2R2, SO2NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12; and
R10 is C1-C4 haloalkyl, (CH2)nC3-C8 cycloalkyl, (CH2)nheterocycle, (CH2)nC3-C8 optionally substituted cycloalkyl, (CH2)n optionally substituted aryl, or (CH2)n optionally substituted heterocycle; or a pharmaceutically acceptable salt thereof.
The present invention also provides novel processes for making, as well as novel pharmaceutical formulations of the compounds of Formula II.
The compounds of Formula I are selective xcex23 receptor agonists and as such are useful for treating Type II diabetes and obesity, as well as useful for stimulating or activating the xcex23 receptor. Therefore, the present invention also provides for methods of treating Type II diabetes and obesity, as well as a method of stimulating or activating the xcex23 receptor.
In addition, the present invention provides the use of compounds of Formulas I for treating Type II diabetes and obesity as well the use of compounds of Formulas I for stimulating or activating the xcex23 receptor.
In addition, compounds of Formula I can be used to prepare a medicament useful for the treatment of Type II diabetes, the treatment of obesity, and the stimulation or activation of the xcex23 receptor.
For the purposes of the present invention, as disclosed and claimed herein, the following terms are defined below. As they relate to the present invention, the terms below may not be interpreted, individually or collectively, to describe chemical structures that are unstable or impossible to construct.
The term xe2x80x9chaloxe2x80x9d represents fluorine, chlorine, bromine, or iodine.
The term xe2x80x9cC1-C4 alkylxe2x80x9d represents a cyclo, straight or branched chain alkyl group having from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and the like. A xe2x80x9chaloalkylxe2x80x9d is one such alkyl substituted with one or more halo atoms, preferably one to three halo atoms. An example of a haloalkyl is trifluoromethyl. An xe2x80x9calkoxyxe2x80x9d is a alkyl group covalently bonded by an xe2x80x94Oxe2x80x94 linkage.
The term xe2x80x9c1 to 5 carbon straight or branched alkylenexe2x80x9d represents a one to five carbon, straight or branched, alkylene moiety. A branched alkylene may have one or more points of branching. A 1 to 5 carbon straight or branched alkylene may optionally be unsaturated at one or more carbons. Thus, a 1 to 5 carbon straight or branched alkylene includes 1 to 5 carbon alkylene, alkenylene and alkylidene moieties. Examples include methylene, ethylene, propylene, butylene, xe2x80x94CH(CH3)CH2xe2x80x94CH(C2H5)CH2xe2x80x94, xe2x80x94CH(CH3)CH(CH3)xe2x80x94, xe2x80x94CH2C(CH3)2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CHxe2x95x90, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, and the like.
The xe2x80x9cacylxe2x80x9d moiety, alone or in combination, is derived from an alkanoic acid containing from one to seven carbon atoms. The term xe2x80x9cacylxe2x80x9d also includes moieties derived from an aryl carboxylic acid.
The term xe2x80x9carylxe2x80x9d represents an optionally substituted or unsubstituted phenyl or naphthyl. The term (CH2)naryl is preferably benzyl or phenyl.
The term xe2x80x9coptionally substitutedxe2x80x9d or xe2x80x9csubstitutedxe2x80x9d as used herein means an optional substitution of one to three, preferably one or two groups independently selected from halo, C1-C4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, CONH(C1-C4 alkoxy), cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, benzyl, nitro, NR11R12, NHCO(C1-C4 alkyl), NHCO(benzyl), NHCO(phenyl), SR2, S(C1-C4 alkyl), OCO(C1-C4 alkyl), SO2(NR11R12), SO2(C1-C4 alkyl), or SO2(phenyl).
R2 is independently hydrogen, C1-C4 alkyl, or aryl.
R11 and R12 are independently H, C1-C4 alkyl, or combine with the nitrogen to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl.
The term xe2x80x9cheterocyclexe2x80x9d represents a stable, optionally substituted or unsubstituted, saturated or unsaturated 5 or 6 membered ring, said ring having from one to four heteroatoms that are the same or different and that are selected from the group consisting of sulfur, oxygen, and nitrogen; and when heterocycle contains two adjacent carbon atoms, the adjacent carbon atoms may be structured to form a group of the formula xe2x80x94CHxe2x95x90CHxe2x80x94; provided that (1) when the heterocyclic ring contains 5 members, the heteroatoms comprise not more than two sulfur or two oxygen atoms but not both; and (2) when the heterocyclic ring contains 6 members and is aromatic, sulfur and oxygen are not present. The heterocycle may be attached at any carbon or nitrogen which affords a stable structure. The heterocycle may be optionally substituted. Examples of a heterocycle include but are not limited to pyrazole, pyrazoline, imidazole, isoxazole, triazole, tetrazole, oxazole, 1,3-dioxolone, thiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, piperazine, morpholine, pyrazine, pyrrolidine, piperidine, oxazolidone, oxazolidinedione, imidazolidinone, and the like.
The term xe2x80x9cleaving groupxe2x80x9d as used in the specification is understood by those skilled in the art. Generally, a leaving group is any group or atom that enhances the electrophilicity of the atom to which it is attached for displacement. Preferred leaving groups are p-nitrobenzene sulfonate, triflate, mesylate, tosylate, imidate, chloride, bromide, and iodide.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d, as used herein, represents an amount of a compound of the invention that is capable of stimulating the xcex23 receptor in mammals. The particular dose of the compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the patient, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
The term xe2x80x9ctreating,xe2x80x9d as used herein, describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, to alleviate the symptoms or complications, or to eliminate the disease, condition, or disorder.
The term xe2x80x9cselectivexe2x80x9d means preferential agonism or stimulation of the D3 receptor over agonism of the xcex21 or xcex22 receptor. In general, the compounds demonstrate a minimum of a twenty fold differential (preferably over a 50xc3x97 differential) in the dosage required to behave as an agonist to the xcex23 receptor and the dosage required for equal agonism of the xcex21 and xcex22 receptors as measured in the Functional Agonist Assay. The compounds demonstrate this differential across the range of doses. Thus, xcex23 selective compounds behave as agonists for the xcex23 receptor at much lower concentrations with lower toxicity by virtue of their minimal agonism of the other receptors.
The term xe2x80x9cstimulatingxe2x80x9d, as used herein, means affecting, activating, or agonizing the xcex23 receptor to elicit a pharmacological response. The stimulation or activation of the receptor may be either complete or partial relative to a known stimulating agent such as isoproterenol.
As previously noted, the present invention provides a method of treating type II diabetes and obesity, comprising administering to a mammal in need thereof compounds of the Formula I.
Preferred embodiments of the present invention are set out in paragraphs below.
(a) R1 is 
(b) R1 is 
(c) R1 is 
(d) R1 is 
(e) R1 is 
(f) R1 is 
(g) R1 is 
(h) R1 is attached to X1 in the 4 position.
(i) R1 is 
(j) R1 is 
(k) R1 is 
(l) R1 is 
(m) X1 is xe2x80x94OCH2xe2x80x94, the oxygen of which is attached to R1.
(n) X1 is a bond.
(o) R3 is methyl.
(p) R3 is hydrogen.
(q) R5 is methyl or ethyl.
(r) R6 is methyl or ethyl.
(s) R5 and R6 are both methyl.
(t) R5 and R6 are both hydrogen.
(u) X2 is isopropylene, methylene, or ethylene.
(v) X2 is isopropylene
(w) X2 is methylene.
(x) X2 is ethylene.
(y) R4 is 
(z) R4 is 
(ab) R4 is 
(ac) R4 is 
(ad) R8 is halo.
(ae) R8 is hydrogen.
(af) R9 is halo, CN, OR10, C1-C4 alkyl, CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), NR2SO2R2, SO2R2, SO2NR11R12, SOR2, optionally substituted aryl, optionally substituted heterocycle.
(ag) R9 is CO2R2, CONR11R12, CONH(C1-C4 alkyl or C1-C4 alkoxy), NR2SO2R2, SO2R2, SO2NR11R12, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12.
(ah) R9 is halo, CN, C1-C4 haloalkyl, SR2, CSNR2, CSNR11R12, SO2R2, SO2NR11R12, SOR2, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12.
(ai) R9 is OR10, optionally substituted aryl, optionally substituted heterocycle, or C2-C4 alkenyl substituted with CN, CO2R2 or CONR11R12.
(aj) R9 is NR2SO2R2.
(ak) R9 is CN.
(al) R9 is CONR11R12.
(am) R9 is OR10.
(an) R10 is (CH2)nC3-C8 cycloalkyl, (CH2)naryl, (CH2)nheterocycle, said aryl, C3-C8 cycloalkyl, or heterocycle being optionally substituted.
(ao) R10 is (CH2)nC3-C8 cycloalkyl, (CH2)nheterocycle, said C3-C8 cycloalkyl, or heterocycle being optionally substituted.
(ap) R10 is (CH2)nheterocycle said heterocycle being unsubstituted or optionally substituted.
(aq) R10 is aryl.
(ar) R10 is pyridyl.
(as) R10 is aryl substituted with CONR11R12, CN, CO2R2, or NR2SO2R2.
(at) R10 is pyridyl substituted with CONR11R12, CN, CO2R2, or NR2SO2R2.
(au) R10 is aryl substituted with CONR11R12.
(av) R10 is aryl substituted with CN.
(ax) R10 is aryl substituted with CO2R2.
(ay) R10 is aryl substituted with NR2SO2R2.
(az) R10 is pyridyl substituted with CONR11R12.
(ba) R10 is pyridyl substituted with CN.
(bb) R10 is pyridyl substituted with CO2R2.
(bc) R10 is pyridyl substituted with NR2SO2R2.
(bd) Preferred optional substitution is halo, C1-C4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, benzyl, nitro, NR11R12, NHCO(benzyl), SO2(C1-C4 alkyl), or SO2(phenyl).
(be) Other preferred optional substitution is halo, C1-C4 haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, nitro, or NR11R12.
(bf) Other preferred optional substitution is halo, hydroxy, carboxy, acyl, COOR2, CONR11R12, cyano, C1-C4 alkoxy, C1-C4 alkyl, phenyl, or NR11R12.
(bg) Other preferred optional substitution is halo, hydroxy, acyl, C1-C4 alkoxy, C1-C4 alkyl, or phenyl.
(bh) Preferred halo groups include bromine, chlorine, or fluorine.
(bi) Other preferred halo groups include chlorine or fluorine.
(bj) Most preferred halo groups include fluorine.
(bk) R7 is hydrogen
(bl) R7 is halo, hydroxy, OR2, C1-C4 alkyl, C1-C4 haloalkyl, aryl, COOR2, CONR2R2, NHCOR2, C1-C4 alkoxy, NHR2, SR2, CN, SO2R2, SO2NHR2, or SOR2.
(bm) R7 is halo, hydroxy, OR2, C1-C4 alkyl, or C1-C4 alkoxy.
Especially preferred compounds include the following: 
By virtue of their acidic moieties, some of the compounds of Formula I include the pharmaceutically acceptable base addition salts thereof. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.
Because of a basic moiety, some of the compounds of Formula I can also exist as pharmaceutically acceptable acid addition salts. Acids commonly employed to form such salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, xcex2-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like salts.
In addition, it is recognized that compounds of the present invention may for a variety of solvates with a number of different solvents. Representative solvates can be useful as final embodiments of the present invention or as intermediates in the isolation or preparation of the final embodiments of this invention. For example solvates can be prepared with lower alcohols such as ethanol and with alkyl esters such ethylacetate.
It is recognized that various stereoisomeric forms of the compounds of Formula I may exist. The compounds may be prepared as racemates and can be conveniently used as such. Therefore, the racemates, individual enantiomers, diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.
The compounds of Formula I can be prepared as described in the following Schemes and Examples. Schemes I and II describe methodology for the preparation of final embodiments of the present invention. Schemes III-VII represent methodology for the preparation of intermediates required for the construction of the final embodiments of the invention. 
In Scheme I, X1, X2, R1, R2, R4, R5, and R6 have the same meaning as previously described; and X3 is a bond. The reaction of Scheme I is carried out under conditions appreciated in the art for the amination of epoxides. For example, the epoxide (A) may be combined with the amine (B) in an alcohol, such as ethanol, at room temperature to the reflux temperature of the reaction mixture. Preferably, the reaction is carried out under conditions generally described in Atkins et al., Tetrahedron Lett. 27:2451 (1986). These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide (DMSO), dioxane, diethylene glycol dimethyl ether (diglyme), tetrahydrofuran (THF), or other polar aprotic solvents in which the reagents are soluble. Preferably, the solvent is DMSO. The reaction is carried out at temperatures ranging from about 0xc2x0 C. to ref lux.
Expoxides utilized in scheme I can be prepared by methods well known in the art, or according to Scheme III from starting material known in the art.
Certain compounds of the present invention are prepared by a novel combinatorial/parallel synthesis. This synthesis is described in Scheme II. 
In Scheme II, X1, X2, R1, R4, and R5 have the same meaning as previously described and R6 is hydrogen. The reaction of Scheme II is preferably carried out by adding to a glass vial: a non-reactive solvent such as methanol, DMF, methylene chloride or acetonitrile, amine (IV), and ketone (V). The solution is shaken to allow for imine formation and treated with Amberlite IRA400 borohydride resin (Aldrich Chemicals). The slurry is then shaken an additional 24 hours to effect reduction to the secondary amine. Methylene chloride and polystyrene-linked benzaldehyde resin (Frechet, J. M. et al., J. Am Chem. Soc. 93:492 (1971)) is added to the vial, in order to scavenge excess primary amine starting material. The slurry is shaken, preferably overnight. The slurry is then filtered through a cotton plug, and the residual solids are rinsed with methanol. Evaporation under a flow of air, followed by drying for several hours at room temperature in a vacuum oven yields the desired product of sufficient purity.
Alternatively, compounds of formula (V) can be prepared by dissolving, in a vial, the amine and ketone in a non-reactive solvent or solvent mixture such as methanol, DMF, or the like. Acetic acid and sodium cyanoborohydride are then added. After being shaken for approximately 72 hours the reaction mixture is applied to an ionexchange column such as SCX. The column is flushed with solvent and the product was then eluted using a solution such as ammonia in methanol. The solvent was evaporated, followed by drying in a vacuum oven to yield the secondary amine product.
A modification of Scheme II is necessary when the amine hydrochloride salt is used. Addition of resin-bound base to the initial reaction mixture prior to reduction or scavenging allows the desired reaction to proceed. Imine formation using amine hydrochloride salts, an aldehyde or ketone, and a resin bound amine base may be carried out using two different resins: poly(4-vinylpyridine), commercially available from Aldrich, and resin (VIII), synthesized by the reaction of Merrifield resin with piperidine (Scheme IIa): 
In Scheme IIa, PS is polysytrene. Both the poly(4-vinylpyridine) and resin (VIII) promote imine formation.
Scheme II can also be carried out by utilization of traditional techniques. Reductive aminations described in scheme II are well known in the art. They are typically performed by mixing the amine and ketone starting materials in a solvent and adding a reducing agent. Solvents typically include lower alcohols, DMF, and the like. A wide variety of reducing agents can be utilized, most commonly utilized are sodium borohydride and sodium cyanoborohydride. The reaction is typically performed at room temperature to the reflux temperature of the solvent. Products are isolated by techniques well known in the art.
The ketone and amino starting materials of Scheme II can be prepared by techniques recognized and appreciated by one skilled in the art. The synthesis of the starting materials is generally described in Schemes III and VII. 
In Scheme III, R1 is the same as previously defined. R13 is OH or SH. Equimolar amounts of the aromatic compound (Compound IX) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (Compound X) are dissolved in an inert solvent such as acetone or DMF and treated with about 1.1 equivalents of a non-reactive acid scavenger, such as K2CO3. The suspension is then heated at reflux for 16-20 hours with stirring. The solvent is removed in vacuo. The residue is partitioned between chloroform or other organic solvent and water. The organic layer is dried over Na2SO4 and concentrated in vacuo to give the compound (XI) in sufficient purity ( greater than 95%) and yield (85-100%).
The epoxide (XI) is dissolved in an alcohol, preferably methanol, and treated with one equivalent of dibenzylamine. The solution is preferably stirred at reflux for three to four hours and then cooled to ambient temperature. Approximately 10 equivalents of ammonium formate are added to the flask, followed by 10% palladium on carbon, and the suspension stirred vigorously at reflux for 30-45 minutes. The reaction mixture is then filtered through Celite, concentrated in vacuo to a minimum volume and treated with 1.1 equivalents of a 1.0 M anhydrous solution of HCl in ether. The solution is concentrated to dryness. The solid residue is triturated with pentane to yield products of sufficient purity ( greater than 97%) and yield (60-100%). If desired, further purification may be carried out by passing over a short plug of silica, eluting with CHCl3, then 95:5 CHCl3/MeOH, then 25:5:1 CHCl3/MeOH/MH4OH.
Alternatively, the epoxide (XI) is treated with a solution of methanol saturated with ammonia gas and stirred at room temperature in a sealed tube for 16 hours. This solution is then evaporated, and the residue subjected to standard purifications such as column chromatography or recrystallization. The HCl salt is then optionally produced by the addition of HCl gas in ether.
The ketone moieties of Scheme II, that are either unknown in the art or not commercially available, can be prepared in accordance with Scheme IV. 
In Scheme IV, R4 and R5 are the same as previously defined. The notationxe2x80x94indicates optional branching. Preferably, R4 is a substituted phenyl. The reaction described in Scheme IV is referred to as a Heck reaction and is described in A. J. Chalk et al., J. Org. Chem. 41: 1206 (1976). The reaction is achieved by treating compound (XIII) with an arylpalladium reagent. The arylpalladium reagent is generated in situ by treating Compound (XIV) with a palladium-triarylphosphine complex. The reaction is generally carried out under conditions appreciated in the art.
Additional amines, of the type where X2 is methylene, R4 is aryl, and R10 is aryl, heterocycle, optionally substituted aryl, or optionally substituted heterocycle, that are reacted in a manner analogous to Scheme I can be prepared in accordance with Scheme V. 
R5, R6, and R10 are as previously defined and X2 is methylene. Compounds of the formula (XVII) can be prepared by reacting 4-hydroxybenzyl alcohol with excess (5 mol/equiv) of a compound of formula (XVIA) by methods well known in the art. (see Sh. Prikl. Kin., Vol 45, 1573-77 (1972); Russ.) The reaction can also be carried out by mixing the reagents in an aprotic solvent, preferably diglyme, and adding potassium t-butoxide (0.5 mol/equiv.). The reaction is then heated to reflux and water removed. After removal of water is complete, generally 2-8 hours depending upon the scale of the reaction, the resulting solution is subjected to aqueous workup including acidic washes and the product is isolated by crystallization. Compound (XVII) can be reduced by methods well known in the art. Compound (XVIII) is preferably prepared by hydrogenation of the corresponding compound (XVII) over a precious metal catalyst. The hydrogenation can be affected at between 20 and 60 psi of hydrogen, and with a variety of solvents, temperatures, and catalysts well known in the art. The reaction is preferably carried out at 50 psi of hydrogen over 5% palladium on carbon wetted with 2B3 ethanol. Compound (XVII) is charged to the reactor along with one equivalent of acetic acid, diluted with methanol, heated to 50xc2x0 C., and subjected to hydrogen for 5-24 hours depending on the scale of the reaction. The product is isolated as the acetic acid salt upon work up by methods well known in the art.
A skilled artisan would appreciate that compound (XVIII) could be coupled with a wide variety of aromatic halides to yield the claimed ethers. The coupling can be carried out according to procedures well known in the art and is preferably performed by mixing the starting materials in N,N-dimethylacetamide and toluene in the presence of potassium carbonate. The reaction is then heated to reflux for 5 to 24 hours and water removed. The product is typically isolated by aqueous work up after rotory evaporation of the reaction solvent. The crude product can be purified by methods well know in the art. A skilled artisan would appreciate that the amines prepared by Scheme V can be utilized in Scheme I to prepare compounds of the present invention.
Other amines used to construct final embodiments of the present invention can be prepared according to scheme VI. 
Compounds of formula (XXI) can be prepared by the addition of a nucleophile, of the formula R6-M, wherein M is a metal or metal salt, to the compounds of formula (XX) according to procedures well known in the art. The skilled artisan would appreciate a wide variety of conditions amenable to performing the additions. Preferred nucleophiles include, but are not intended to be limited to, alkyl grignard reagents, alkyl lithium reagents, and the like.
Compounds of formula (XXII) can be prepared from the compounds of formula (XXI) by the Ritter reaction. (See Organic Reactions, Vol. 17, pp. 213-325, (1979)).
Compounds of formula (XXIII) can be prepared by reduction of the compounds of formula (XXII) according to procedures well known in the art. Preferred reducing agents include, but are not intended to be limited to, borane complexes and the like.
Compounds of formula (XXIV) can be prepared by reduction of the compounds of formula (XXIII) according to procedures well known in the art. (See Greene T. W., Protective Groups in Organic Synthesis, John Wiley and Sons, (1981)).
Other amines used to construct final embodiments of the present invention can be prepared according to scheme VII, wherein J is a protecting group. 
The compounds of formula (XXVI) can be prepared from the amino esters of formula (XXV) by methods well known in the art. (see, Greene supra).
The amides of formula (XXVII) can be prepared from the N-protected amino acids of formula (XXVI) by methods well known in the art. For example, any number of peptide coupling procedures will affect the desired reaction. (see March, Advanced Organic Chemistry, 3 ed.)
The deprotection of the compounds of formula (XXVII) can be accomplished by methods well known in the art. (see, Greene supra). 
Compound (IXXX) can be prepared by the addition of phenyl hydrazine to 1,3-cyclohexanedione by methods known in the art. For example, phenylhydrazine or it salt can be dissolved in water and cyclohexanedione added. The addition is preferably carried out in a dropwise fashion at room temperature. Other methods of addition and temperatures, however, would be operable. After stirring for 4-24 hours, the resulting precipitate can be collected by filtration and purified by methods known in the art.
Compound (XXX) can be prepared by the cyclization of compounds of formula (IXXX) by methods known in the art. For example, the transformation can be affected by heating the compound of formula (IXXX) in the presence of an acid such as phosphoric acid, sulfuric acid, trifluoracetic acid, and the like. While the reaction can be affected at lower temperatures, the reaction is preferably performed at about 90xc2x0 C., for about 1-2 hours, in neat phosphoric acid.
Dehydrogenation of the compound of formula (XXX) yield 4-hydroxycarbazole can be accomplished by methods well known in the art. For example, the compound of formula (XXX) can be reacted with rainey-nickel, copper bromide, or palladium on carbon. The preferred conditions include stirring with 5% or 10% palladium on carbon in cymene and dodecene. The skilled artisan would appreciate that such a transformation can be performed at a range of temperatures, the progress of which is typically monitored by TLC or other analytical techniques.
Compound of formula (XXXII) can be prepared from 4-hydroxycarbazole by methods well known in the art. For example, equimolar amounts of the 4-hydroxycarbazole and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate can be dissolved in an inert solvent such as acetone and treated with 1.1 equivalents of a non-reactive acid scavenger, such as potassium carbonate or cesium carbonate. The suspension is then heated at reflux for about 16-20 hours with stirring. The solvent can be removed in vacuo. The residue is partitioned between chloroform or other organic solvent and water. The organic layer can be dried over Na2SO4 and concentrated in vacuo to give the compound (XI) in sufficient purity ( greater than 95%) and yield (85-100%).
Alternatively, 4-hydroxycarbazole can be reacted with epichlorohydrin, by methods known in the art and the resulting product can be closed to the epoxide compound of formula (XXXII) by methods well known in the art.
Starting materials for the compounds described in Schemes I-VIII, as well as starting materials for the Preparations and Examples included herein, are either commercially available, known in the art, or can be prepared by methods known in the art or described herein.
Another embodiment of the present invention is a process of preparing novel compounds of the formula IA; 
wherein:
A3 is CH or N;
which comprises:
in step 1, hydrolysis of a compound of the formula IB; 
and, optionally, in step 2, reacting the product of step 1 with an acid to form an acid addition salt.
Step one of the process can be carried out by a variety of agents known in the art. It is, however, preferably affected by utilization of one of the following agents: polyphosphoric acid, H2O2 and K2CO3 in dimethylsulfoxide, H2O2 and ammonium hydroxide, H2O2 and sodium hydroxide, potassium hydroxide and t-butanol, or water and mineral or organic acid. Step 2 of the process involves addition of an agent capable of forming an acid addition salt with the product of step 1. Step 2 can be carried out by numerous methods known in the art involving addition of mineral acid, or other acid, to a solution of the product of step 1. Additionally, the product of step one could be purified prior to step 2 and the present invention contemplates such an optional purification step.
Another embodiment of the present invention is a process of preparing a compound of Formula I which comprises:
In step 1, reacting an epoxide of the formula XI: 
with an amine of formula (B): 
and optionally in step 2, reacting the product of step 1 with an acid to form an acid addition salt.
The process can be carried out by a variety of agents known in the art or described herein, it is however preferably affected by reacting the amine and epoxide in a solvent at elevated temperature. Preferred solvents include: lower alcohols, dimethylformamide, dimethylsulfoxide, acetone and the like. The reaction is generally performed at a temperature ranging from ambient to the reflux temperature of the solvent. Most preferably, it is done in ethanol at 40-60xc2x0 C. Step 2 can be carried out by numerous methods known in the art involving addition of mineral acid, or other acid, to a solution of the product of step 1. Additionally, the product of step one could be purified prior to step 2 and the present invention contemplates such an optional purification step.
The following examples and preparations are provided merely to further illustrate the invention. The scope of the invention is not construed as merely consisting of the following examples. In the following examples and preparations, melting point, nuclear magnetic resonance spectra, mass spectra, high pressure liquid chromatography over silica gel, gas chromatography, N,N-dimethylformamide, palladium on charcoal, tetrahydrofuran, ethyl acetate, thin layer chromatography and elemental analysis are abbreviated M.Pt., NMR, MS, HPLC, GC, DMF, Pd/C, THF, EtOAc, TLC and EA respectively. The terms xe2x80x9cEAxe2x80x9d, xe2x80x9cTLCxe2x80x9d, xe2x80x9cNHRxe2x80x9d, and xe2x80x9cMSxe2x80x9d, when being utilized in the preparations, indicate that the data indicated was consistent with the desired structure.
Preparations 1 through 24 describe syntheses of compounds utilized in combinatorial scheme II.

4-Bromo-1-(2-oxazolidine)benzene (3.0 g, 13.3 mmol), 3-buten-2-ol (1.4 g, 20 mmol), Pd(OAc)2 (60 mg, 0.26 mmol), (o-tolyl)3P (158 mg, 0.52 mmol), sodium bicarbonate (1.34 g, 15.9 mmol) in 30 mL of N-methylpyrrolidinone were heated under nitrogen at 130xc2x0 C. for 1 hour. The reaction mixture was then cooled and partitioned between ethyl acetate and water. The combined organic layers were washed with water and then dried (Na2SO4), filtered, and concentrated in vacuo to yield 2.6 g of a tan oil. Purification by flash chromatography (silica gel, 1:1 ethyl acetate/hexane) yielded 1.9 g of a pale yellow oil which crystallized upon drying under vacuum. Recrystallization from hexane gave 1.47 g (49%) of white needles, m.p. 62-64xc2x0 C. NMR. MS.

4-Fluorobenzonitrile (6.05 g, 50mmol), 4-(4-hydroxyphenyl)-2-butanone (8.21 g, 50mmol) and potassium carbonate (8.3 g, 60mmol) were dissolved in N,N-dimethylacetamide (50 mL) and heated at 150xc2x0 C. for 4 hours under nitrogen. The reaction mixture was then poured into 800 mL of ice water. A slowly crystallizing solid was filtered to give 13 g of crude product. This material was recrystallized from ethanol/water (3:1) to give 10.48 g (79%) of pale brown crystals, m.p. 64-66xc2x0 C. EA. NMR. MS.

4-[4-(3-Oxobutyl)phenoxy]benzonitrile (6.0 g, 22.6mmol) and potassium carbonate (1.0 g, 7.2 mmol) were slurried in DMSO (50 mL) and cooled to 0xc2x0 C. in an ice bath. Aqueous 30% hydrogen peroxide (6 mL) was added slowly, and the mixture stirred at 0xc2x0 C. for 1 hour. The reaction was quenched by pouring into 500 mL water, and the subsequent white precipitate was collected and washed with water. This material was recrystallized from 300 mL ethanol to give 5.35 g (84%) white crystals, m.p. 169-172xc2x0 C. NMR. MS. EA.
5-Chloromethyltetrazole (1.19 g, 10 mmol) in CH2Cl2 (10 mL) was treated with triphenylmethyl chloride (2.79 g, 10 mmol) and diisopropylethylamine (2.0 mL, 11.5 mmol) and stirred for 40 minutes at room temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate/water. The organic layer was washed with saturated NaHCO3 solution, then brine, dried (Na2SO4) and concentrated in vacuo to yield 3.48 g of an off-white solid. Trituration of this residue in diethyl ether yielded 3.04 g (84%) of a white solid, m.p. 162-165xc2x0 C. NMR. MS. EA.

4-(4-Hydroxyphenyl)-2-butanone (493 mg, 3 mmol) was cooled to 5xc2x0 C. and treated with NaH (180 mg, 4.5 mmol, 60% in mineral oil) under nitrogen. After 15 minutes the ice bath was removed and the solution allowed to warm to room temperature over 45 minutes. The reaction was cooled to 5xc2x0 C. and treated with 2-triphenylmethyl-5-chloromethyltetrazole (1.08 g, 3 mmol) and stirred at room temperature for 3 hours. The reaction mixture was poured into EtOAc (300 mL), and washed with water then brine. The organic layer was dried (MgSO4) and concentrated in vacuo to provide a yellow solid. This material was suspended in a mixture of MeOH (100 mL) and THF (50 mL) and treated with 4N HCl in dioxane (7.5 mL, 30 mmol). The resulting mixture was stirred for 1.5 hr. and then concentrated in vacuo to provide a tan solid. The residue was applied to a silica chromatography column and eluted with 33-100% ethyl acetate in hexane to provide 235 mg (32%) of a white solid, m.p. 148-150xc2x0 C. NMR. MS. EA.

4-(4-Hydroxyphenyl)-2-butanone (4.11 g, 25 mmol) and potassium carbonate (10.37 g, 75 mmol) in acetone (30 mL) was treated with 3-picolyl chloride hydrochloride (4.27 g, 26 mmol) under nitrogen. The mixture was stirred at reflux for 21 hours, proceeding about 50% towards completion. Potassium iodide (2.0 g, 13 mmol, 0.5 eq) was added and after 3 hours no picolyl chloride was observed on TLC. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc/water. The combined organic layers were washed with water, saturated NaHCO3 solution, 10% Na2SO3, and then brine. The organic layer was dried (MgSO4) and concentrated in vacuo to provide 4.8 g of a yellow oil. The material was purified on a Waters Prep 2000LC by elution with 10-80% ethyl acetate in hexanes over 45 minutes to yield 2.20 g (34%) of an oil which solidified on standing, m.p. 35-37xc2x0 C. NMR. MS. EA.

4-(4-Hydroxyphenyl)-2-butanone (4.93 g, 30 mmol) was added to a solution of sodium methoxide (1.62 g, 30 mmol) in methanol (150 mL) under nitrogen. After stirring for 1 hour the methanol was removed in vacuo and the residue suspended in acetone (200 mL). The suspension was treated with 4,6-dimethoxy-2-chlorotriazine and refluxed for 3 hours. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate/water. The organic layers were dried (MgSO4) and concentrated in vacuo to provide 10.28 g of a white semi-solid. The material was purified on a Waters Prep 2000LC by elution with a gradient of 20-60% ethyl acetate in hexanes over 55 minutes to yield 4.43 g (49%) of a colorless oil. NMR. MS. EA.

4-(4-Hydroxyphenyl)-2-butanone (3.28 g, 20 mmol) in anhydrous DMF (150 mL) was treated with NaH (1.2 g, 30 mmol, 60% in mineral oil) under nitrogen. The solution was stirred for 30 minutes at ambient temperature and then treated with 6-chloronicotinamide (3.13 g, 20 mmol). The reaction was stirred at 60xc2x0 C. for 1.5 hours and then 90xc2x0 C. for five hours. The reaction was allowed to cool, poured into 50% saturated ammonium chloride solution, and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo with a xylene azeotrope to yield 11.4 g of a brown oil. The material was purified on a Waters Prep 2000LC by elution with 75-100% EtOAc over 60 minutes. The resulting material was triturated in cold EtOAc and collected by filtration to provide 2.73 g (48%) white solid m.p. 137-139xc2x0 C. EA. NMR. MS.

In a manner similar to the above examples, 3-(4-hydroxyphenyl)-2-propanone (2.25 g, 15 mmol) was treated with NaH (0.9 g, 22.5 mmol, 60% in mineral oil) followed by reaction with 6-chloronicotinamide (2.34 g, 15 mmol). Following workup the material was purified on a Waters Prep 2000LC to provide 1.28 g (32%) of a light yellow solid. m.p. 172-174xc2x0 C. NMR. MS. EA.

A mixture of methyl cyclohexanone-2-carboxylate (11.0 g, 70 mmol, from Fluka), a-bromo-p-tolunitrile (12.3 g, 63 mmol), potassium carbonate (10.5 g, 76 mmol) in THF (200 mL) was refluxed for 24 hours. The progress of the reaction was followed by GC. The reaction was diluted with water and the THF was removed under reduced pressure. The aqueous portion was extracted with EtOAc, dried (MgSO4), and concentrated to give 19.3 g of a white solid that was 74% pure by gas chromatrophy. The solid was recrystallized from hexane/EtOAc to give 7.75 g white crystals that were 100% pure by glc. A second crop of 3.65 g was obtained by adding more hexane to the filtrate. Overall, 11.4 g (67%) of 1-[(4-cyanophenyl)methyl]-1-methoxycarbonyl-2-oxocyclohexane carboxylate, was obtained; mp 82-84xc2x0 C. NMR. MS.
Under a blanket of nitrogen, a mixture of 1-[(4-cyanophenyl)methyl]-1-methoxycarbonyl-2-oxocyclohexane carboxylate (7.6 g, 28 mmol), sodium cyanide (2.1 g, 42 mmol) and DMSO (100 mL) was heated at 115xc2x0 C. for 1.5 hours. The progress of the reaction was monitored by glc. The reaction was cooled and partitioned between water, EtOAc and brine. The organic layer was washed with water and dried (MgSO4). After concentration, crude product was obtained as a tan oil. Purification by plug filtration (200 g silica gel, 15% EtOAc/hexane) gave 3.3 g (55%) product as colorless oil. NMR. MS.

A DMSO (20 mL) solution of the compound of Preparation 28 (2.5 g, 11.7 mmol) was cooled in an ice bath. Solid K2CO3 (500 mg) was added followed immediately by 30% H2O2 (3 mL). After 20 minutes, TLC (3/7 EtOAc/hexane) showed a trace of starting material remained. The ice bath was removed and the reaction was stirred and room temperature for 1 hour. The reaction was diluted with 500 mL water and the white solid collected and dried to give 2.44 g (90%) desired amide. The product was recrystallized from 1/9 EtOAc/hexane to give 2.02 g of the titled product as white crystals, mp 167-170xc2x0 C. NMR. MS.
6-aromo-2-tetralone g, 8.89 mmol) was dissolved in toluene (50 mL) and treated with excess ethylene glycol (4.88 mL, 88.9 mmol) and catalytic p-toluenesulfonic acid (15 mg). The solution was stirred at reflux 16 hours, and water was removed from the reaction mixture using a Dean-Stark condenser. After cooling to ambient temperature, the toluene solution was washed 2xc3x971N NaOH, 1xc3x97water, 1xc3x97brine, dried over Na2SO4 and concentrated in vacuo to give 2.23 g (93%) of 6-bromo-2-tetralone ethylene ketal as a brown oil which was used without further purification.
6-Bromo-2-tetralone ethylene ketal (2.2 g, 8.15 mmol) was dissolved in anhydrous THF (30 mL), cooled to xe2x88x9278xc2x0 C. and treated with tert-butyllithium (12.05 mL, 20.4 mmol, 1.7M in pentane) under an atmosphere of nitrogen. After stirring for 30 minutes, anhydrous carbon dioxide gas was passed through the reaction mixture for 20 minutes at xe2x88x9278xc2x0 C. The suspension was then allowed to warm to ambient temperature. The solution was quenched with water and acidified with 1N HC1, then extracted 2xc3x97EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to a pale brown oil. The oily residue was applied to a silica flash chromatography column and eluted with 30%-50% EtOAC in hexanes to yield tetralone-6-carboxylic acid, ethylene ketal 1.06 g (55%) of a slowly crystallizing solid. NMR. MS.

Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was codissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0xc2x0 C. and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Ammonium chloride (333 mg, 6.23 mmol) and triethylamine (1.58 mL, 12.5 mmol, d=0.797) were added. The solution was stirred at ambient temperature for 16 hours. The suspended urea and salts were filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 250 mg (64%) of 2-tetralone-6-carboxamide, ethylene ketal as a white solid, clean by NMR, TLC.
2-Tetralone-6-carboxamide ethylene ketal (250 mg, 1.07 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. The volatiles were removed in vacuo and the residue triturated in ethyl acetate. The solids were filtered, washed and dried to yield 77.5 mg (38%) of 2-tetralone-6-carboxamide as a white powder, pure by NMR, TLC. MS.

2-Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was co-dissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0xc2x0 C. and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Morpholine (0.91 mL, 10.4 mmol, d=0.998) was added and the solution stirred at ambient temperature for 16 hours. The suspended urea was filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 323 mg (51%) of 2-tetralone-6-morpholinamide, ethylene ketal as a slowly crystallizing solid, clean by NMR, TLC.
2-Tetralone-6-morpholinamide, ethylene ketal (323 mg, 1.06 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. TLC indicated a mixture of 2-tetralone-6-morpholinamide, ethylene ketal and desired product, so the solution was heated to reflux for 16 hours. The volatiles were removed in vacuo and the residue applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 27 mg (10%) of 2-tetralone-6-morpholinamide a slowly crystallizing solid, pure by NMR, TLC. MS.
The following compounds were prepared in a manner analogous to schemes IV and/or preparations 1 through 14 described herein or by techniques appreciated in the art:

A mixture of 4-hydroxybenzyl alcohol (100.08 g, 806 mmol), 2-nitropropane (400 mL, 4.45 mol), and diglyme (800 mL) was heated to 38xc2x0 C. Potassium t-butoxide (45.29 g, 403.6 mmol) was added, and the mixture was heated to reflux at 132xc2x0 C. with a Dean-Stark trap. Water began collecting in the trap, and continued at a high rate for approximately 1.5 h. When water collection slowed (around 2.5 h) then aliquats of solvent (30-40 mL each) were removed every thirty minutes. During the water collection and solvent removal the temperature rose from 132xc2x0 C. to 149xc2x0 C. After 4 h less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis. The heating mantle was removed, and the reaction mixture was allowed to cool. When the temperature was 100xc2x0 C. water (200 mL) was added, and the solution was allowed to cool to room temperature. The solvent was removed on a rotary evaporator under vacuum until 593 g of solution remained. Water (500 mL) and EtOAc (500 mL) were added and the layers were separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL). The organic layer was distilled in vacuo to 261 g of oil to which EtOAc was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 min, and the product crystallized to yield a beige solid (112.36 g, 71% yield,  greater than 98% purity by HPLC analysis). Another crop of crystals may be obtained from the filtrate by concentrating and filtering the solids, or by concentrating more fully to a solution and adding heptane to crystallize. NMR, MS, and EA.

A one-gallon high-pressure reactor was charged with 4-(2-methyl-2-nitropropyl)phenol (120 g, 614 mmol), HOAc (35.2 mL, 614 mmol), 5% Palladium on carbon (24 g) wetted with 2B3 EtOH (60 mL), and MeOH (1230 mL). The mixture was heated to 50xc2x0 C. with agitation (600 rpm), and the reactor was purged with N2 and pressurized to 50 psi with H2. After 15.5 h the reactor was purged with N2, and the cooled mixture was filtered. The filter cake was washed with MeOH and the filtrate was concentrated to 514 g of slurry on a rotary evaporator. To this slurry was added EtOAc (2 L) with vigorous agitation. After stirring for 1 h, the resulting crystals were filtered and washed with a small amount of EtOAc. The product was dried overnight in a 45xc2x0 C. vacuum oven to yield 118.83 g (86%) of product as small white needles (mp 211-216xc2x0 C. dec). This material was 99% pure by HPLC analysis, and while another 9.00 g of material was obtained from the mother liquor it was found to be only 88% pure. NMR. EA.

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g, 200 mmol), powdered K2CO3 (69.1 g, 500 mmol), 6-chloronicotinamide (31.32 g, 200 mmol), DMAC (622 mL) and iso-octane (70 mL) was slowly heated to reflux at 140xc2x0 C. A water trap filled with iso-octane was used to collect water formed in the reaction, and reflux was maintained for 5.5 h. The mixture was allowed to cool to room temperature, and the solids were filtered and washed with EtOAc. The filtrate was concentrated in vacuo to 88.6 g of solid which was dissolved in EtOAc (500 mL). To this solution was added water (800 mL), 1N HCl (200 mL) and MeOH (50 mL). The pH of this mixture was adjusted to 7.2 with con. HCl, and the aqueous layer was separated and washed with methyl t-butyl ether (500 mL). The product was crystallized by addition of 10N NaOH (20 mL) which raised the pH to 11. This pH was maintained by addition of 10N NaOH as needed during the course of the crystallization (90 min). The product was filtered, washed with water and dried in vacuo at 45xc2x0 C. to 53.11 g (93%) of white solid which was  greater than 98% pure by HPLC analysis: 1H NMR (300 MHz, DMSO-d6) NMR was consistent with the desired product.

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (45.06 g, 200 mmol), powdered K2CO3 (69.1 g, 500 mmol), and DMAC (550 mL) was heated to 75-100xc2x0 C. Toluene (166 mL) was added, and the mixture was slowly heated to reflux at 134xc2x0 C. The reflux temperature was raised by distillation of toluene and water into a water trap until the temperature reached 141xc2x0 C. The mixture was then allowed to cool to below 100xc2x0 C. at which point 4-fluorobenzonitrile (24.46 g, 202 mmol) was added along with 50 mL of toluene. The mixture was again heated to reflux at 140xc2x0 C. with water being collected in a toluene-filled water trap for 4 h. The mixture was allowed to cool to room temperature, and the solids were filtered and rinsed with toluene. The filtrate was concentrated on a rotary evaporator to 77 g of syrup which was dissolved in EtOAc (400 mL). This solution was extracted with water (400 mL), and the aqueous layer was back-extracted with EtOAc (100 mL). The combined organic layers were washed with water (3xc3x97400 mL) and concentrated in vacuo to 53.4 g (100%) of oil which was  greater than 98% pure by HPLC analysis. NMR.

Aqueous 30% H2O2 (62.1 mL, 548 mmol) was added dropwise to a mixture of 4-(4-(2-amino-2-methylpropyl)phenoxy)benzonitrile (53.2 g, 200 mmol), K2CO3 (15.78 g, 114 mmol) and DMSO (270 mL) over 20 min while the temperature was held at 20xc2x0 C. with a cooling bath. The mixture was stirred at this temperature for 1 h after the addition was complete, and then water (209 mL) was added slowly. The slurry was cooled in an ice bath with stirring for 1 h, and the product was then filtered, washed with water and dried in vacuo at 50xc2x0 C. to yield 55.0 g (97%) of white solid. Analysis by HPLC indicated purity of  greater than 99%. NMR.

A mixture of 4-(2-amino-2-methylpropyl)phenol acetic acid salt (22.53 g, 100 mmol), powdered K2CO3 (34.55 g, 250 mmol) and DMAC (275 ml) was heated to 100xc2x0 C. Toluene (94 ml) was added and the mixture slowly heated to reflux. The reflux temperature was raised by distillation of toluene and water until it reached 140xc2x0 C. The mixture was then cooled to below 100xc2x0 C. and 2-chloronicotinonitrile (13.86 g, 100 mmol) added with a toluene rinse (50 ml). The mixture was again heated to reflux and the reflux temperature raised to 140xc2x0 C. as before. Then the water trap was filled with toluene and the reflux continued for 40 min., at which point HPLC showed no 2-chloronicotinonitrile remained but the reaction was not complete. After cooling the reaction below reflux, additional 2-chloronicotinonitrile (0.63 g, 4.5 mmol) was added and reflux continued for 90 min. The reaction was cooled to room temperature and the solids filtered with a toluene wash. The filtrate was concentrated on a rotary evaporator to 41 g of syrup which was dissolved in EtOAc (200 ml). This solution was washed with water (200 ml) and the aqueous layer back-extracted with EtOAc (50 ml). The combined organic layers were washed with water (3xc3x97200 ml) and concentrated in vacuo to 26.93 g of solid, xcx9c100% of theory. HPLC indicated 94.3% purity. 1H NMR (300 MHz, DMSO-d6) was consistent with the desired product.

A solution of 4-(2-amino-2-methylpropyl)aniline hydrochloride salt (1.0 g, 4.98 mmol) in anhydrous DMF (30 mL) was treated with benzenesulfonyl chloride (880 mg, 4.98 mmol). The solution was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was washed twice with hexane. The insoluble material was dissolved in water and extracted twice with ethyl ether to remove any remaining neutral impurities. The aqueous layer was separated and basified with excess 1N sodium hydroxide. Upon standing, a crystalline solid soon precipitated. The solid was collected, and dried under vacuum at 60xc2x0 C. to provide 570 mg (38%) of the desired product as a white crystalline solid. Mp 180-181xc2x0 C.

A solution of (S)-4-(oxiranylmethoxy)-9H-carbazole (215.5 mg, 0.9 mmol) in methanol (25 ml) was treated with dibenzylamine (520 ml, 2.7 mmol) and stirred at reflux for 4 h. The solution was cooled to ambient temperature, treated with 10% palladium on carbon (400 mg) and ammonium formate, (2.0 g, 31.7 mmol) and heated to reflux for 4 hours. The suspension was cooled and filtered through a pad of celite, and the filtrate concentrated in vacuo. The residue was purified by flash chromatography over silica eluting with CHCl3:MeOH (95:5) and then CHCl3:MeOH:NH4OH (25:5:1) to give a white solid (140 mg, 61%). NMR

A mixture of 4-(2-methyl-2-nitropropyl)phenol (3.0 g, 15.4 mmol), ethylbromoacetate (2.04 mL, 17.0 mmol) and potassium carbonate (6.4 g, 46.2 mmol) was stirred at room temperature for 18 h. The reaction was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (3xc3x97). The combined organic layers were washed with water (3xc3x97), brine, dried (Na2SO4), and concentrated in vacuo to a brown oil. The material was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3 to provide 4.22 g (97%) of a clear oil. NMR

A solution of ethyl(4-[2-methyl-2-nitropropyl]phenoxy)ethanoate (3.6 g, 12.8 mmol) in ethanol (35 mL) was charged with platinum oxide (0.72 g) and hydrogenated on a Parr shaker using 60 psi of hydrogen for 72 h at room temperature. The catalyst was filtered and the solution concentrated in vacuo. The resulting residue was purified by flash chromatography over silica gel eluting with5% MeOH/CHCl3/NH3 to provided 0.9 g (28%) of a clear oil. MS (FD+): m/z 251.

N-benzyl-4-hydroxyphenethylamine (J. Het. Chem., p. 839, 1971; 7.26 g, 0.032 mol) and 6-chloronicotinamide (5.0 g, 0.032 mol)were dissolved in 180 ml of dimethylacetamide and heated to reflux while water was collected in a Dean-Stark trap prefilled with isooctane. The reaction was refluxed under nitrogen for 17 hrs and additional 6-chloronicotinamide (1 g) added. After 2 hours, the solvent was removed in vacuo and the residue dissolved in 125 ml of ethyl acetate. The solution was shaken with dilute HCl and the solids collected by filteration (8.2 g). NMR.

Ethyl-3-iodo-4-fluorobenzoate (2.28 g, 7.75 mmol) and the acetic acid salt of 4-(2-amino-2-methylpropyl)phenol (1.75 g, 7.75 mmol) were dissolved in N,N-dimethylacetamide (40 ml) and toluene (20 ml) and treated with potassium carbonate (3.2 g, 23.3 mmol, 3 eq.). The mixture was heated with vigorous stirring at 125xc2x0 C. for 16 hours. The crude reaction mixture was diluted with ethyl acetate (100 ml), washed with water (2xc3x97) then brine (1xc3x97), dried with Na2SO4, filtered, and concentrated in vacuo to afford the biphenyl ether as a golden oil(3.15 g, 93%). NMR. MS.

Potassium carbonate (24 g) was added to a solution of of 2-methoxy phenol (18.94 g, 0.152 mol) in acetone (500 ml) at room temperature. A solution of bromoacetonitrile (17.43 g, 0.145 mol) in acetone (500 ml) was then added and the resulting suspension was heated at reflux for 10 h. The reaction vessel was then cooled and the solution was concentrated under reduced pressure and taken up into water (150 ml). Chloroform (250 ml) was added and the two layers separated. The organic phase was washed with brine (100 ml) and 10% aqueous NaOH (100 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the product (19.91 g, 80%) as an oil. 1H NMR (CDCl3, 250 MHz) 7.0 (4H m), 4.8 (2H, s), 3.9 (3H, s).

A solution of the 2-cyanomethoxyanisole (5.6 g, 0.034 mol) in anhydrous ammonia (25 ml) and ethanol (50 ml) was heated to 120xc2x0 C. at 500 psi for 12 h in the presence of raney nickel (1.4 g). The reaction mixture was filtered, concentrated under reduced pressure, the residue taken up in ether, and washed with 1.2 M HCl. The acidic phase was then rendered basic (pH=12) with careful addition of solid KOH and the alkaline solution extracted with ether. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the product (1.99 g, 35%) as an oil. IR. NMR. MS.

Titled compound was prepared substantially in accordance with Example 94 by starting with 4-fluorophenylmethylsulfone (3.1 g, 17.75 mmol) to yield product (4.67 g) after purification as a tan solid. NMR.

The phenol from preparation 16 (2.9 g, 13 mmol), 4-fluorophenyl-2-trifluoromethyl-methylsulfone (2.9 g, 13 mmol), and potassium carbonate (4.2 g, 30 mmol) were heated to 100xc2x0 C. in 50 ml of dimethylacetamide. After 17 hours, the reaction mixture was cooled, filtered, and concentrated in vacuo. The residue was purified by column chromatography to yield 1.9 g of pale yellow oil. NMR.

A mixture of 4-hydroxybenzoic acid (3.50 g, 25 mmol), 4-fluorobenzonitrile (3.00 g, 35 mmol), and powdered K2CO3 (6.80 g, 49 mmol) were heated in DMAC (50 mL) at 140xc2x0 C. for 20 hours. The cooled mixture was then acidified with 1N HCl and extracted with EtOAc (3xc3x9750 mL). Concentration of the extracts in vacuo left a residue which was chromatographed over silica gel (5% MeOH/CHCl3) to provide 2.30 g (39%) of pure product. MS (FD+) 238.9.

Titled compound was prepared substantially in accordance with Example 94 by starting with 2-fluoropyridine (1.72 g, 17.75 mmol) to yield product (1.28 g) after purification as a brown oil. EA. NMR.

4-(4xe2x80x3-Cyanophenoxy)benzoic acid (1.00 g, 4.2 mmol) was dissolved in THF (40 mL) followed by the addition of 1,1-carbonylidimidazole (0.745 g, 4.6 mmol) in small portions. This mixture was stirred for 1 hour whereupon 1,2-diamino-2-methylpropane (0.48 mL, 4.6 mmol) was added and the resultant mixture stirred for 20 hours at RT. The mixture was then concentrated in vacuo and the residue chromatographed over silica (10% MeOH/CHCl3) to provide 0.50 g (38%)of the desired product. MS. (FD+) 310.2 m.p. 133-137xc2x0 C.

A mixture of 4-(2-methyl-2-nitropropyl)phenol (5.00 g, 25.6 mmol), 4-fluorobenzaldehyde (3.17 g, 25.6 mmol), and powdered K2CO3 (4.00 g, 29 mmol) were heated in DMAC (50 mL) at 140xc2x0 C. for 20 hours. The cooled mixture was then diluted with water and the organics extracted with EtOAc (3xc3x9750 mL). Concentration of the extracts in vacuo left a residue which was chromatographed over silica gel (5% MeOH/CHCl3) to provide 6.15 g (80%) of pure product. MS(FD+) 299. EA.

4-(4-(2-Methyl-2-nitropropyl)phenoxy)benzaldehyde (6.00 g, 20 mmol) was dissolved in chloroform (500 mL). m-Chloroperoxy-benzoic acid (10.0 g, 58 mmol) was added in small portions at RT. After stirring for 1 hour, the mixture was concentrated in vacuo and MeOH (300 mL) added followed by the dropwise addition of conc. HCl (5 mL). This mixture was stirred for 3 hours at RT and then concentrated in vacuo. Chromatography over silica gel (MeOH/CHCl3) allowed for the isolation of 3.20 g (55%) of the desired product. MS(FD+): 287.2.

A mixture of NiCl2.6H2O (1.40 g, 5.9 mmol) in MeOH (100 mL) was stirred at RT under a nitrogen atmosphere. Sodium borohydride (0.675 g, 17.9 mmol) was carefully added to the mixture in small portions. Twenty minutes after complete addition of the initial sodium borohydride 4-(4-(2-methyl-2-nitropropyl)phenoxy)phenol (3.20 g, 11 ntnol) was added followed by the careful portionwise addition of Inore NaBH4 (1.58 g, 42 mmol) which caused a frothing exothermic reaction. All starting nitro compound had been consumed within 15 minutes of the last hydride addition as judged by TLC analysis. The mixture was then filtered through Celite and the filtrate concentrated in vacuo. The resulting residue was chromatographed over silica gel (MeOH/CHCl3) which allowed for isolation of both the incompletely reduced hydroxylamine product (0.675 g, 22%) and the desired amine product (0.94 g, 34%). MS (FD+): 258 (amine)

Ethylbromoacetate (4.17 g, 25 mmol) was added to a mixture of 4-benzyloxyphenol (5.00 g, 25 mmol) and K2CO3 (3.50 g, 25 mmol) in DMF (75 mL) and stirred for 20 hours at ambient temperature. The mixture was then concentrated in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was further extracted with 2xc3x9750 mL of EtOAc and the combined extracts were washed with 2xc3x9750 mL of water and dried over Na2SO4. Concentration of the organic solution in vacuo left 7.00 g (97%) of product as a white solid. m.p. 65-68xc2x0 C.

Ethyl-4-benzyloxyphenoxyacetate compound (3.50 g, 12.2 mmol) was placed in a PARR bottle along with EtOAc (75 mL), EtOH (75 mL), and 5% Pd/C (1.20 g) and the mixture placed under 40 psi of H2. The reaction was shaken under pressure for 4 hours after which no starting material remained by TLC. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to give 2.35 g (97%) of the desired phenol. MP.

Ethyl-4-hydroxyphenoxyacetate (1.35 g, 6.9 mmol) was combined with N-(t-butoxycarboxy)ethanolamine (1.00 g, 6.2 mmol), triphenylphosphine (1.79 g, 6.8 mmol) and DEAD (1.30 mL, 8.3 mmol) in THF (50 mL) and stirred for 35 hours at RT. The solvent was removed in vacuo and the resulting residue chromatographed over silica gel (30-40% EtOAc/Hexanes) which resulted in recovery of a phenol/product mix. Subsequent chromatography over silica gel (1% MeOH/CHCl3) allowed for the isolation of the desired product as an oil 0.870 g (41%). MS (FD+): 339. EA.

Ethyl-4-(2-t-butylcarboxyethyl)phenoxyacetate (0.80 g, 2.35 mmol) was stirred for two hours at RT with TFA (2 mL) in dichloromethane (20 mL). The mixture was then quenched into aqueous NaHCO3 and the organics extracted with 3xc3x9720 mL of dichloromethane. The combined extracts were concentrated in vacuo and the resulting residue chromatographed over silica gel (CHCl3) which allowed for isolation of 0.50 g (89%) of the desired amine as a thick oil. MS (FD+): 239.
To a suspension of 4-(3-methyl-3-aminobutyl) methyl benzoate hydrochloride (3.01 g), sodium carbonate (3.71 g, 3.0 eq.), 30 mL of dioxane, and 30 mL of water at 0xc2x0 C. was added di-t-butyldicarbonate (2.55 g, 1 eq.) in 5 mL of dioxane. The resulting solution was allowed to stir for 1.5 hours. The reaction was diluted with and partitioned between ethyl acetate and water. The aqueous layer was removed and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography eluting with 25% ethyl acetate/toluene to give 2.81 g of the title compound. Yield: 75%.
To a solution of N-butyloxycarbonyl-4-(3-methyl-3-aminobutyl) methyl benzoate (1.9 g) in 20 mL of ethanol was added 12 mL of 5N sodium hydroxide (10 eq.). The resulting solution was allowed to stir for 3 hours. The solvent was concentrated in vacuo and the residue was taken up in water. The resulting alkaline solution was neutralized with 5N hydrochloric acid (3 mL). This mixture was extracted twice with ethyl acetate and the extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.59 g of the title compound. Yield: 87%. 1H NMR.
To a solution of N-butyloxycarbonyl-4-(3-methyl-3-aminobutyl) benzoic acid (1.9 g) in 5 mL of pyridine under a nitrogen atmosphere was added thionyl chloride (0.036 mL, 1.1 eq.). The resulting solution was allowed to stir until TLC indicated conversion of the starting acid to the acid chloride. 4-Aminobenzamide (44 mg, 1 eq.) was then added and the resulting solution was allowed to stir for 4 hours. The solvent was removed in vacuo and the crude product was recrystallized from ethanol to give 62 mg of the title compound.
Yield: 45%. 1H NMR.
N-Butyloxycarbonyl-4-(3-methyl-3-aminobutyl) benzoic acid piperidyl amide
To a flame dried flask under a nitrogen atmosphere was added N-butyloxycarbonyl-4-(3-methyl-3-aminobutyl) benzoic acid (500 mg), piperidine (0.161 mL, 1.0 eq.), 1-hydroxybenzotriazole (47 mg, 1.0 eq.), diisopropylethylamine (0.2 mL, 3.5 eq.), and 25 mL of methylene chloride. A solution of (dimethylaminopropyl)ethyl carbodiimide in 20 mL of methylene chloride was then added and the resulting solution was allowed to stir for 1 hour before diluting with ethyl acetate. This mixture was acidified with 10% aqueous citric acid. The organics were washed twice each with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate and was washed twice with 10% aqueous sodium bicarbonate, once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound.

To a flame dried flask under a nitrogen atmosphere was added N-(benzamid-4-yl)-Nxe2x80x2-butyloxycarbonyl-4-(3-methyl-3-aminobutyl)benzamide (370 mg), 10 mL of methylene chloride, and trifluoroacetic acid (0.67 mL, 10.0 eq). The resulting solution was allowed to stir for about 18 hours. The pH was adjusted to 7 with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 260 mg of the title compound. Yield: 92%. MS(FD): 326 (M+1) 1H NMR.

N-Butyloxycarbonyl-4-(3-methyl-3-aminobutyl) benzoic acid piperidyl amide (540 mg) was converted to the titled product substantially in accordance with procedure 113 except that after final concentration the residue is redissolved in 1N hydrochloric acid. This acidic solution was made basic with 5N sodium hydroxide and extracted twice with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 284 mg of the title compound. Yield: 72%. MS(FD): 275 (M+1). 1H NMR.

A mixture 4-(2-oxopropyl)phenol (101.03 g, 673 mmol), (R)-(+)-xcex1-methylbenzylamine (91.1 mL, 706 mmol), wet (60 % (w/w) H2O) 2% Pt, 8% Pd/C (8.42 g, 5 wt % dry load), and EtOH (560 mL) was placed in an autoclave which was pressurized to 50 psi with hydrogen at 23xc2x0 C. After stirring for 4 h, the mixture was filtered, and the filtrate was concentrated on a rotary evaporator to 179 g of thick oil. This oil was dissolved in CH2Cl2 (1300 mL), and 2N HCl (363 mL) was added which caused precipitation of the hydrochloride salt. This mixture was stirred for 2 h, filtered, washed with CH2O2 and 2N HCl, and was dried in a 45xc2x0 C. vacuum oven to yield 135.96 g (69%) of a white solid. The optical purity of the material was determined by GC analysis and-was shown to be 93.7% de. A small portion of this material (10.02 g) was suspended in CH2Cl2 (65 mL), and concentrated NH4OH (6.7 mL) and water (10 mL) were added which caused the solid to dissolve. The pH was then lowered to 0.2 with con. HCl, and the slurry was filtered, washed with water and CH2Cl2 and dried as above to give 9.47 g (94% recovery) of product as a white solid (mp 224xc2x0 C. [dec]). NMR. MS (FD+) m/z 256 (39%), 148 (100%)

A hastalloy autoclave was charged with (2R)-1-(4-hydroxyphenyl)-2-(N-[(R)-a-methylbenzyl])amino propane hydrochloride (72.3 g, 248 mmol), 5% Pd/C (16.0 g, wetted with 100 mL of EtOH), and MeOH (400 mL). The autoclave was pressurized to 50 psi H2 and heated to 50xc2x0 C. for 6 h with vigorous stirring. After cooling, purging with nitrogen and filtering the mixture, the filtrate was concentrated on a rotary evaporator under vacuum. The resulting oily foam was dissolved in a minimal amount of MeOH and was triturated by addition of EtOAc. The solid was filtered, and another crop of solid which precipitated from the filtrate was also collected. The combined solids were dried in a 45xc2x0 C. vacuum oven overnight to yield 34.2 g (73%) of a white solid. MP 160xc2x0 C. [dec]. MS(FD+) m/z 151 (92%).

A 3-L flask was charged with (2R)-1-(4-hydroxyphenyl)-2-aminopropane hydrochloride (50.0 g, 266 mmol), powdered K2CO3 (91.91 g, 665 mmol), 6-chloronicotinamide (41.65 g, 266 mmol) and dry ( less than 0.1% H2O) DMAC (1 L). The mixture was heated to 140-142xc2x0 C., and a steady stream of nitrogen was passed through the flask and out of the distillation apparatus. After 4.5 h, 415 mL of distillate had been collected, and the mixture was cooled to 15xc2x0 C. The potassium salts were filtered and the filter cake was washed with DMAC (200 mL). The filtrate was concentrated under vacuum with an 80xc2x0 C. water bath. Xylenes (250 mL) were added to the residue and the solution was concentrated as above to yield 107 g of solid. This product was crystallized from refluxing methyl-t-butyl ether (500 mL) which was allowed to cool slowly to 23xc2x0 C. over 3 h. The solid material was filtered, washed with MTBE (200 mL) and dried in a 45xc2x0 C. vacuum oven to provide 69.91 g of solid. This product was taken up in refluxing toluene (1738 mL) which caused an oil to form in solution. The stirring was stopped to allow the oil to settle to the flask sides, and the flask was then removed from the heating mantle. The hot toluene solution was decanted from the oil into another flask, and the solution was allowed to cool to ambient temperature with stirring over the course of 4 h. The resulting precipitate was filtered, rinsed with toluene (200 mL) and was dried in a 45xc2x0 C. vacuum oven to yield 55.40 g (77%) of material as a white solid (mp 140-141xc2x0 C.). 1H NMR. MS(FAB) m/z 272.1393.

To a solution of 2-bromo-4-fluoroanisole (20.0 g, 97.6 mmol) in 100 mL of tetrahydrofuran at xe2x88x9255xc2x0 C. to xe2x88x9265xc2x0 C. was added n-butyllithium (2.5 M in hexanes, 39 mL) via syringe. After 15 minutes, triisopropylborate (25 mL, 110 mmol) was added and the resulting solution was allowed to warm to xe2x88x9225xc2x0 C. at which point 1N hydrochloric acid was added. The quenched reaction was stirred for 15 minutes, diluted with 200 mL of ethyl acetate, and the 2 layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give a pale yellow semi-solid which was triturated with hexane to give 6.8 g of the title compound.
Yield: 41%. 1H NMR. MS(FD)

A mixture of 4-fluoroanisole-2-boronic acid (3.3 g, 19.4 mmol), 2-nitrobromobenzene (3.56 g, 17.6 mmol), triphenylphosphine (367 mg, 1.4 mmol), triethylamine (4.6 g, 45.8 mmol), and 40 mL of dimethylformamide was sparged with nitrogen for 5 minutes before adding palladium acetate (160 mg, 0.7 mmol) and heating the mixture to 100xc2x0 C. for 5 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was shaken with 0.1N sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed by 4% ethyl acetate/hexanes to give 7.5 g of the title compound. Yield: 86%. EA. MS(FD).

A mixture of 2-(2-nitrophenyl)-4-fluoroanisole (427 mg, 1.73 mmol) and triethyl phosphite (3 mL) was heated to reflux for 3.5 hours. The reaction was cooled and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 2% ethyl acetate/hexanes followed by 5% ethyl acetate hexanes to give 212 mg of the title compound.
Yield: 57%. MS(FD).

A mixture of 1-fluoro-4-methoxycarbazole (438 mg, 2.04 mmol) and pyridine hydrochloride (3 g) was placed into an oil bath that was preheated to 220xc2x0 C. After 20 minutes, the reaction was poured onto a mixture of ice and concentrated ammonium hydroxide. The product was extracted into ethyl acetate and the extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was azeotroped with toluene to give 470 mg of the title compound.
Yield:  greater than 100%. MS(FD).

A mixture of 1-fluoro-4-hydroxycarbazole (470 mg, 2 mmol), potassium carbonate (345 mg, 2.5 mmol), (2R)-(xe2x88x92)-glycidyl 3-nitrobenzenesulfonate, (518 mg, 2 mmol), and 20 mL of acetone was heated to reflux for about 18 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash silica gel chromatography eluting with 10% ethyl acetate/hexanes to give 247 mg of the title compound.
Yield: 48%. 1H NMR. MS(FD).

A solution of 2-fluorophenylhydrazine hydrochloride (24.8 g, 152.5.6 mmol) in 225 mL of water and 2.25 mL of isopropanol was added dropwise to a solution of 1,3-cyclohexanedione (17.1 g, 152.5 mmol) in 117 mL of water and 1.1 mL of isopropanol. Sodium bicarbonate (12.6 g, 152.5 mmol) was then added. After 3 hours, the orange powder that formed was collected, washed with 200 mL of water, and dried at 45xc2x0 C. in a vacuum oven to give 31.5 g of the title compound. Yield: 94%. 1H NMR. MS(FD).

To phosphoric acid (85%, 150 mL) at 90xc2x0 C. was added a solution of N-(2-fluorophenyl)cyclohexenol-3-hydrazide (30.5 g, 138.5 mmol) in 150 mL of phosphoric acid (85%) dropwise. The resulting solution was heated at 90xc2x0 C. for 1 hour then cooled to room temperature. Ethanol (250 mL) was added and the quenched reaction mixture was poured into 600 mL of water. This mixture was stirred for 1 hour before the pH was adjusted to 5 with 50% aqueous sodium hydroxide. The alkaline mixture was extracted with ethyl acetate (1 L) and the extract was washed with brine, shaken with celite, filtered, and concentrated in vacuo. The residue was purified via flash silica gel chromatography eluting with 40% ethyl acetate/hexanes followed by 50% ethyl acetate/hexanes to give 2.8 g of the title compound. Yield: 10%. EA. MS(FD).

A mixture of 1-fluoro-5-oxo-5,6,7,8-tetrahydrocarbazole (111 mg, 0.55 mmol), copper II bromide (244 mg, 1.09 mmol), and 5 mL of ethyl acetate was heated to reflux for about 12 hours. The reaction was cooled to room temperature, treated with celite, and then filtered. The reaction was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 5 mL of dimethylformamide and lithium carbonate (52 mg, 0.7 mmol) and lithium bromide (61 mg, 0.7 mmol) were added. The resulting mixture was heated to reflux for 1.5 hours. The reaction was concentrated in vacuo and the crude product was purified via flash silica gel chromatography eluting with 15% ethyl acetate/hexanes to give 32 mg of the title compound. Yield: 18%. 1H NMR. MS(FD).

1-Fluoro-5-hydroxycarbazole (25 mg, 0.124 mmol) and (2R)-(xe2x88x92)-glycidyl 3-nitrobenzenesulfonate, (32 mg, 0.124 mmol) were converted to 25 mg of the title compound substantially in accordance with the procedure of Preparation 122. Yield: 65%. 1H NMR. MS(FD).

The titled compound can be prepared by procedures known in the art or by utilizing procedures substantially in accordance with preparations 123-126 provided phenyl hydrazine is utilized as a starting material in preparation 123 instead of fluorophenyl hydrazine.
See the following references to obtain 2-benzoyl-1,2,3,9-tetrahydro-4H-pyrido[3,4-b]indol-4-one 
Cain, M.; Mantei R.; Cook, J. M.; J. Org. Chem., 1982, 47, 4933-4936. Hagen, T. J.; Narayanan, K.; Names J.; Cook, J. M.; J. Org. Chem., 1989, 54, 2170-2178.
For 4-(oxiranylmethoxy)-9H-pyrido[3,4-b]indole as percurser to xcex2-adrenergic blockers see the following: Corbiere, J.; Fr. Demande FR 2,516,512; Nov. 19, 1981 (CA99:175742q)

To a warm solution of 2-benzoyl-1,2,3,9-tetrahydro-4H-pyrido [3,4-b]indol-4-one (11.10 g, 38.2 mmol) in dioxane (240 mL) was added 5N NaOH (360 mL) and the mixture refluxed for 2 hr. The reaction was allowed to cool and separate into two layers. The aqueous layer was extracted with EtOAc (3xc3x97200 mL). All the organic portions were combined and washed with brine (300 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the crude product. The material was recrystillized from MeOH to give 5.53 g (78%) of a reddish brown solid. m.p. 220-233xc2x0 C. decomposed. NMR. FD. EA.

To a mixture of 1,2,3,9-tetrahydro-4H-pyrido[3,4-b]indol-4-one (1.86 g, 10 mmol), dodecene (2.78 mL, 12.5 mmol) and 10% Pd on carbon (750 mg) in 2-methoxyethyl ether (50 mL) was heated at 150xc2x0 C. for 3 hr. The reaction was filtered while hot through a celite pad and then a majority of the 2-methoxyethyl ether was evaporated in vacuo. The resulting residue was absorbed on silica and chromatographed on a flash column by eluting with EtOAc and then 9 EtOAc/1 MeOH to give 1.65 g (90%) of a yellow foam. NMR. FD.